Recently, a research paper entitled “Microbiota-derived urocanic acid triggered by tyrosine kinase inhibitors potentiates cancer immunotherapy efficacy” was published in Cell Host & Microbe and selected as the cover paper. Dr. Mengying Zhang, a PhD student of State Key Laboratory of Natural Medicines, was the first author, and academician Guangji Wang, researcher Fang Zhou and associate researcher Yunlong Shan were the co-corresponding authors, while Associate Researcher Le Zhen and Senior Laboratory Technician Ying Peng made significant contributions to this study.
Journal Cover
Although Immune Checkpoint Inhibitor (ICI) has demonstrated impressive efficacy in clinical applications, however, in the field of solid tumor treatment, the response rate of patients to ICI is only 10-30%. The results of several clinical studies suggest that combining ICI therapy with tyrosine kinase inhibitors (TKIs) has significant therapeutic potential and is expected to bring new therapeutic hope to tumor patients. However, the potential mechanism of action of this combination therapy is still not completely clear.
Given that TKIs are orally administered drugs, they are bound to interact with intestinal flora in the body. Based on the drug in vivo process assay, the team found that TKIs in the gut enhance ICI efficacy by increasing the levels of Muribaculum gordoncarteri and its secondary metabolite Urocanic acid (UCA). Specifically, UCA covalently binds to IκBα, thereby inhibiting the activation of the NF-κB pathway. This process further led to a decrease in CXCL1 expression in tumor vascular endothelial cells, which ultimately inhibited the recruitment of Myeloid-derived suppressor cells (MDSC) mediated by the CXCL1-CXCR2 axis. Taken together, this study elucidated a novel mechanism by which TKIs drive gut flora metabolism to assist ICI efficacy, and also revealed that UCA and M. gordoncarteri can serve as biomarkers of ICI responsiveness.
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This study was supported by the “Metabolic Regulation and Drug Target Discovery” of the National Natural Innovation Group Program of China, the International Cooperation Program of the National Natural Science Foundation of China, the Top-level Program of the National Natural Science Foundation of China, the National Natural Science Foundation of Jiangsu Province, and the Three Projects of Shenzhen Medical and Healthcare.
Original link: https://www.cell.com/cell-host-microbe/abstract/S1931-3128(25)00155-6
